Phase I Study of Carfilzomib and Panobinostat for Patients with Relapsed and Refractory Myeloma: A Multicenter MMRC Clinical Trial Jonathan L. Kaufman, Todd Zimmerman, Cara A. Rosenbaum, Anuj Mahindra, Ajay Nooka, Leonard T. Heffner, R. Donald Harvey, Charise Gleason, Colleen Lewis, Cathy Sharp, Kenisha Barron, and Sagar Lonial
Study Rationale Multiple myeloma (MM) remains a disease with a need for new treatments for patients with relapsed and refractory disease Carfilzomib is a selective proteasome inhibitor that has demonstrated significant activity in patients with relapsed and refractory myeloma Panobinostat is a pan-deacetylase inhibitor that can overcome resistance in combination with bortezomib in refractory multiple myeloma patients. Based on data showing synergistic cytotoxicity of pandeacetylase and proteasome inhibitors, we hypothesized that carfilzomib and panobinostat would be safe and effective for the treatment of relapsed/refractory multiple myeloma.
Study Design Objectives and Assessments - Primary Endpoint: Determine MTD and optimal schedule of the combination - Secondary Endpoints: Adverse event incidence, frequency and severity Response data including response rates, duration, progression free and overall survival - Multi-center, open-label, Phase 1 study: Dose escalation phase: Standard 3 + 3 design to determine MTD MTD based on DLT during Cycle 1 Patients assigned to one of 4 cohorts Expansion phase: 12 additional patients treated at the MTD to support the secondary objectives.
Carfilzomib/Panobinostat Dosing schedule PAN CAR 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Dex Week 1 Week 2 Week 3 Week 4 PAN: Panobinostat 15-20 mg orally CAR: Carfilzomib 20 45 mg/m 2 ; all doses of carfilzomib over 27mg/m 2 were infused over 30 minutes Dex: Dexamethasone 4 mg oral for first cycle, optional thereafter If 3 out of 4 week dosing was not tolerable a change to 2 of 4 week dosing was planned
Dose Escalation Schedule Cohort Panobinostat (oral TIW 3 out of 4 weeks Carfilzomib (IV Days 1/2, 8/9, and 15/16 every 4 weeks) 1 15 mg C1D1/2: 20 mg/m 2 thereafter: 27 mg/m 2 2 20 mg C1D1/2: 20 mg/m 2 thereafter: 27 mg/m 2 Dexamethasone (oral prior to carfilzomib) 4 mg (Cycle 1: thereafter as clinically indicated) 4 mg (Cycle 1: thereafter as clinically indicated) 3 20 mg C1D1/2: 20 mg/m 2 thereafter: 36 mg/m 2 4 mg (Cycle 1: thereafter as clinically indicated) 4 20 mg C1D1/2: 20 mg/m 2 thereafter: 45 mg/m 2 4 mg (Cycle 1: thereafter as clinically indicated)
Patient Characteristics N = 26 1 Female, % 50 Median age, in years (range) 65 (49-75) ECOG performance status, % 0-1 / 2 96 / 4 Bortezomib (BTZ) refractory (%) 16 (62) IMiD refractory (%) 22 (85) Median lines of therapy (range) 3 (1-7) Prior Auto (%) 23 (88) Pts received multiple prior regimens, including multiple prior BTZ combinations 1 20 patients in the dose escalation phase and 6 patients in the dose expansion phase
Results: Cohorts, DLTs and MTD Cohort Evaluable DLT Non evaluable 1 3 0 1 - progression 2 3 0 1 - missed doses, non toxicity related 3 6 1 - Acute kidney injury, thrombocytopenia 1 - progression 4 5 1 thrombocytopenia 2 - diarrhea One grade 5 cardiac event (sudden cardiac arrest) in cohort 1 was possibly related to study medications MTD is Cohort 3: Carfilzomib 20/36 mg/m 2 and panobinostat 20 mg TIW 3 of 4 weeks
Adverse Events Occurring in 20% (all grades) of patients (n = 26) All 26 (100%) Pan/Bor/Dex 1 Nausea 17 ( 65%) 60% Anemia 14 ( 54%) 47% Diarrhea 13 ( 50%) 71% Thrombocytopenia 13 ( 50%) 66% Fatigue 10 ( 38%) 69% Vomiting 9 ( 35%) Hypokalemia 8 ( 31%) 22% Pyrexia 8 ( 31%) Decreased appetite 7 ( 27%) Hypocalcemia 7 ( 27%) Insomnia 6 ( 23%) 1. Richardson et al; Panorama 2; Blood: 122 (14), 2013.
Adverse Events Occurring in 5% (grade 3/4) of patients (n = 26) AE, regardless of relationship to study drugs Grade 3/4 Number of Subjects with at Least One Event 20 (77%) Pan/ Bor/Dex 1 Anemia 10 (38%) 15% Thrombocytopenia 10 (38%) 64% Neutropenia 5 (19%) 15% Fatigue 3 (12%) 20% Decreased appetite 2 ( 8%) Diarrhea 2 ( 8%) 20% Elevated creatinine 2 ( 8%) Hyperglycemia 2 ( 8%) Hypertension 2 ( 8%) Hyponatremia 2 ( 8%) 1. Richardson et al; Panorama 2; Blood: 122 (14), 2013.
Relative Dose Intensity Cohort 1 2 3 4 Carfilzomib 20/27 20/27 20/36 20/45 N 4 4 13 5 Mean (%) 100 96 98 89 Panobinostat 15 20 20 20 Mean (%) 94 92 93 90
Preliminary Efficacy Data Best confirmed response N = 26 (%) BTZ Refractory N = 16 (%) Overall response (CR + VGPR + PR) 12 (46) 7 (44) Complete response 1 (4) 1 (6) VGPR 5 (19) 1 (6) Partial response 6 (23) 5 (31) MR 3 (12) 1 (6) SD 4 (15) 3 (19) PD 6 (23) 4 (25) All responses occurred in the first 2 cycles Two patients maintained response for 18 months Median DOR is 7.5 months and 8 patients remain on treatment 1 patient was not evaluable for response
Patient Disposition Prolonged study participation N = 26 Patients ongoing 8 (31%) Off treatment 18 (69%) In follow-up 12 (46%) Off study 6 (23%) Death 5 (19%) Withdrew consent 0 (0%) Lost due to follow up 1 (4%) Pts have been on study an average of 4.6 mos (range < 1-20) 14 (78%) pts discontinued treatment secondary to progression 4 (22%) pts discontinued to AE; 1 death; 2 asthenia; 1 GI toxicity
Median PFS is 11.4 months Median PFS is 11.4 months (95% CI is 6.8 16 months) With a median f/u of 8.7 months over 80% of patients are alive
Conclusions & Future Directions The combination of carfilzomib and panobinostat is safe and effective with manageable adverse events in patients with relapsed and refractory myeloma The MTD of the combination in this study is carfilzomib 36mg/m 2 3 of 4 weeks and panobinostat at 20 mg TIW 3 of 4 weeks No unexpected toxicities were seen At the MTD patients were able to tolerate more than 90% of the planned doses Tolerance, response rate, DOR, PFS and OS are favorable when compared to similar studies using different dosing strategies, Shah et al (ASH 2012) and Berdeja et al (ASH 2013)
Acknowledgements Patients and their family and caregivers Investigators and study staff Novartis and Onyx for generous support ACT oncology